Although chronic infection with hepatitis C (HCV) and B viruses (HBV) are important risk factors for hepatocellular carcinoma (HCC), their relative roles in causing liver cancer remain poorly defined, particularly in developed Western countries. Thirty-one patients with HCC seen at the Clinical Center of the National Institutes of Health between 1986 and 1992 were evaluated serologically for evidence of HBV and HCV infection: antibodies to HBV and HCV and hepatitis B surface antigen (HBsAg) were detected by conventional immunoassays, and HCV RNA and HBV DNA were detected by polymerase chain reaction (PCR). Serologic evidence of HBV infection was found in 18 patients (56%), 17 with antibodies, 16 with HBV DNA, and 14 with HBsAg. Evidence of HCV infection was found in 10 patients (32%), seven of whom also had HCV RNA. One patient had both anti-HCV and HBsAg. In comparison to patients with HBV-related HCC, those with HCV-related cancer were older and more likely to be white, to have been born in the United States, to have a history of parenteral exposure, and to have cirrhosis. In two patients in whom the course of hepatitis C could be traced from its onset, hepatocellular carcinoma developed after 5 years in one and after 9 years in another case. Thus chronic HCV infection is a common etiology of cirrhosis among United States patients with HCC, often as a late complication of intravenous drug abuse or blood transfusion.